Treatment of Cellulitis with Cephalexin and Doxycycline
For typical nonpurulent cellulitis, cephalexin monotherapy is the appropriate treatment—adding doxycycline provides no additional benefit and is unnecessary unless specific MRSA risk factors are present. 1
Why Cephalexin Alone Is Sufficient
Beta-lactam monotherapy succeeds in 96% of uncomplicated cellulitis cases because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, both of which are reliably covered by cephalexin. 1 High-quality randomized controlled trials demonstrate that adding trimethoprim-sulfamethoxazole to cephalexin does not improve cure rates compared to cephalexin alone (83.5% vs 85.5%, difference -2.0%, 95% CI -9.7% to 5.7%). 2, 3 The same principle applies to doxycycline—combination therapy adds no clinical benefit for typical cellulitis. 1
MRSA is an uncommon cause of typical cellulitis, even in high-prevalence settings, making routine MRSA coverage with doxycycline inappropriate. 1
Correct Dosing and Duration
- Cephalexin: 500 mg orally every 6 hours (four times daily) 1
- Duration: Exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe 1
- Traditional 7-14 day courses are outdated—5-day courses are equally effective as 10-day courses for uncomplicated cellulitis 1
When Doxycycline Is Actually Indicated
Add doxycycline (100 mg orally twice daily) PLUS cephalexin only when specific MRSA risk factors are present: 1
- Penetrating trauma or injection drug use 1
- Purulent drainage or exudate visible on examination 1
- Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1
- Systemic inflammatory response syndrome (SIRS): fever >38°C, heart rate >90, respiratory rate >24 1
Critical caveat: Doxycycline must never be used as monotherapy for cellulitis because it lacks reliable activity against beta-hemolytic streptococci, which are the most common pathogens. 1 If MRSA coverage is needed but you want single-agent therapy, use clindamycin 300-450 mg orally four times daily instead, which covers both streptococci and MRSA. 1
Common Pitfall to Avoid
The most frequent error is reflexively adding MRSA coverage (doxycycline, trimethoprim-sulfamethoxazole) for typical cellulitis without specific risk factors. 1 This represents overtreatment, increases antibiotic resistance, exposes patients to unnecessary adverse effects (doxycycline causes photosensitivity and GI upset), and provides no clinical benefit. 1 Reserve combination therapy exclusively for the specific scenarios listed above.
Essential Adjunctive Measures
Beyond antibiotics, these interventions accelerate resolution:
- Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema 1
- Examine interdigital toe spaces for tinea pedis, fissuring, or maceration and treat if present to eradicate colonization 1
- Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema 1
When to Reassess or Escalate
Reassess within 24-48 hours to verify clinical response. 1 If the patient shows no improvement or worsening despite appropriate therapy, consider:
- Unrecognized abscess requiring drainage (obtain ultrasound if uncertain) 1
- MRSA infection despite initial assessment—switch to vancomycin 15-20 mg/kg IV every 8-12 hours if hospitalized 1
- Necrotizing fasciitis (severe pain out of proportion to exam, skin anesthesia, rapid progression)—requires emergent surgical consultation and broad-spectrum IV antibiotics (vancomycin plus piperacillin-tazobactam) 1